Benzisothiazolyl-substituted aminomethyl chromanes for treating diseases of the central nervous system

ABSTRACT

The present invention relates to chromans, to processes for their preparation and to their use in medicaments, in particular as agents for treating disorders of the central nervous system.

The present invention relates to chromans, to processes for theirpreparation and to their use in medicaments, in particular as agents fortreating disorders of the central nervous system.

Chromans having affinity to or agonistic action at the serotoninreceptor of subtype 5HT₁ or 5HT_(1A) in particular for treatingdisorders of the central nervous system are known from DE-A-195 43 476,EP-A-0 352 613, EP-A-0 749 970 and WO 99/26621.

BAY x3702,(−)-2-(4-{[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]amino}butyl)-1,2-benzisothiazol-3(2H)-one1,1-dioxide hydrochloride (non-proprietary name: repinotanhydrochloride) is undergoing clinical development for the indicationsskull-brain trauma and stroke (De Vry et al. Drugs Fut. 1997, 22,341-349).

Surprisingly, it has been found that metabolites of repinotan also bindto the 5HT_(1A) receptor.

Accordingly, the invention relates to novel compounds of the generalformula (I),

in which

-   -   the radicals R¹, R² and R³ are as defined below:

R¹ R² R³ OH H H; H OH H; H H OH; OH OH H; OH H OH; H OH OH or OH OH OH,

The compounds according to the invention may exist in stereoisomericforms which are related either as image and mirror image (enantiomer),or which are not related as image and mirror image (diasteromers). Theinvention relates both to the enantiomers or diasteromers and to theirrespective mixtures. These mixtures of enantiomers and diasteromers canbe separated in a known manner to the stereoisomerically pureconstituents.

The compounds according to the invention can also be present in the formof their salts, hydrates and/or solvates.

In the context of the invention, preferred salts are physiologicallyacceptable salts of the compounds according to the invention.

Physiologically acceptable salts of the compounds according to theinvention can be acid addition salts of the compounds with mineralacids, carboxylic acids or sulfonic acids. Particular preference isgiven, for example, to salts with hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonicacid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonicacid, acetic acid, propionic acid, lactic acid, tartaric acid, citricacid, fumaric acid, maleic acid or benzoic acid.

Hydrates of the compounds according to the invention are stoichiometriccompositions of the compounds or its salts with water.

Solvates of the compounds according to the invention are stoichiometriccompositions of the compounds or its salts with solvent.

-   -   if appropriate in an isomeric form, and salts thereof.

Preference is given to compounds of the general formula (I) having the Rconfiguration in the 2-position of the chroman radical.

The R configuration in the 2-position of the chroman radical can beillustrated by the formula below:

The compounds of the general formula (I) according to the invention canbe prepared as illustrated in the formula schemes below and as describedin the working examples:

The compounds according to the invention can be used as active compoundsin medicaments. The compounds according to the invention haveparticularly high affinity to cerebral 5-hydroxytryptamine receptors ofthe 5-HT_(1A) type.

The compounds described in the present invention are thus activecompounds for treating diseases which are characterized by disorders ofthe serotoninergic system, in particular in involvement of receptors ofthe 5-HT_(1A) type. They are therefore suitable for the treatment ofdisorders of the central nervous system such as states of anxiety,tension and depression, central nervous system-related sexualdysfunctions and sleep disorders, and for the regulation of pathologicaldisorders related to the intake of food, stimulants and addictivesubstances. They are furthermore suitable for removing cognitivedeficits, for improving learning and memory performances and fortreating Alzheimer's disease.

These active compounds are furthermore also suitable for modulating thecardiovascular system. They also intervene in the regulation of cerebralperfusion and are thus effective agents for controlling migraine.

Moreover, the compounds of the general formula (I) and thepharmaceutical compositions derived from these compounds can, as hasbeen shown in WO 99/26621 for other 5HT_(1A) ligands, be used forpost-acute therapeutic treatment of multifarious neurological disorderswhere different cell types of the nervous system are degenerated and/orhave been damaged as a result of neurodegenerative disorders orinterventions or exposures. Compounds of the general formula (I) can beused in particular for treating sequelae in which cells of the nervoussystem have been damaged by surgical interventions, infections, exposureto toxic agents, tumors, malnutrition or metabolic disorders. Moreover,compounds of the general formula (I) can be used for treating theeffects of neurodegenerative disorders such as Parkinson's disease,multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, drug abuseor drug addiction (alcohol, cocaine, heroin, amphetamine or the like),myelopathies and/or spinal injuries, dystrophy or degeneration of theneutroretina (retinopathies) and peripheral neuropathies, such asdiabetic neuropathy and/or peripheral neuropathies induced by toxins.Moreover, compounds of the general formula (I) can be used in connectionwith surgical implantations of tissue and/or prostheses for treatingAlzheimer's disease or other neurological disorders and/or dysfunctionswhere an implantation is indicated.

The in vitro action of the compounds according to the invention can bedemonstrated in the following assays:

1. Affinity to the 5-HT_(1A) Receptor

(Dompert et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 1985, 328,467-470).

In this test, binding of [³H]-8-OH-DPAT to 5-HT_(1A) receptors inhippocampus membranes of rats is measured. It was found that thecompounds according to the invention compete with the radio ligand forthe binding site, inhibiting it.

TABLE B Compound of Example K_(i) (nmol/l) 1 3.15 2 1.93

In the binding test, IC₅₀ values are determined which state at whichconcentration of test substance 50% of bound radio ligand is displaced.Taking into account the dissociation constants and the concentration ofradio ligand, this is used to calculate the inhibition constant K_(i).

That the compounds according to the invention are suitable for treating,for example, stroke or skull-brain trauma can be shown in the followinganimal models.

2. Permanent Focal Cerebral Ischemia

Animal model: permanent focal cerebral ischemia (“middle cerebral arteryocclusion”=MCA-O). MCA occlusion in rodents is a widely accepted animalmodel of stroke. Literature: Bederson et al., Stroke, 1986, 17, 472-476.

To cause permanent focal cerebral ischemia, the left middle cerebralartery in rats is occluded by electrocoagulation. The resulting infarctvolume in cortical (subcortical) regions supplied by the middle cerebralartery is used as a measure for the extent of the stroke-inducedneuronal damage.

Substance application: after the occlusion as a continuous i.v infusion(4 hours) of the test substance, started directly after the operation.For evaluation, the animals are sacrificed 7 days after the operation.

In the present invention also includes pharmaceutical preparationswhich, in addition to inert non-toxic pharmaceutically suitableauxiliaries and carriers, comprise one or more compounds of the generalformula (I), or which consist of one or more active compounds of theformula (I), and processes for preparing these preparations.

In these preparations, the active compounds of the formula (I) should bepresent in a concentration of from 0.1 to 99.5% by weight, preferablyfrom 0.5 to 95% by weight, of the total mixture.

In addition to the active compounds of the formula (I), thepharmaceutical preparations may also comprise other pharmaceuticallyactive compounds.

The pharmaceutical preparations mentioned above can be prepared in acustomary manner by known methods using, for example, theauxiliary/auxiliaries or carrier/carriers.

In general, it has been found to be advantageous to administer theactive compound(s) of the formula (I) in total amounts of about 0.01 toabout 100 mg/kg, preferably in total amounts of about 1 mg/kg to 50mg/kg, of body weight per 24 hours, if appropriate in the form of aplurality of individual administrations, to obtain the desired result.

However, it may be advantageous, if appropriate, to deviate from theamounts mentioned, depending on the nature and the body weight of thepatient treated, on the individual response to the medicament, on thenature and severity of the disorder, on the nature of the preparationand the application, and on the time or interval at which administrationtakes place.

WORKING EXAMPLES Example 1

(R)-(−)-2-(4-{[(7-Hydroxy-6-methoxy-3,4-dihydro-2H-chromen-2-yl)methyl]-amino}butyl)-1,2-benzisothiazol-3(2H)-one1,1-dioxide hydrochloride

Step a):

Ethyl 7-(benzyloxy)-6-methoxy-4-oxo-4H-chromen-2-carboxylate

A mixture of 0.37 mmol of1-[2-hydroxy-5-methoxy-4-(phenylmethoxy)-phenyl)]ethanone [Beutler etal., J. Med. Chem. 41, 2333 (1998)] and 1.38 mmol of diethyl oxalate in2 ml of ethanol is, at room temperature, added over a period of 5minutes to 1.1 ml of a sodium ethoxide solution prepared from 0.5 g ofsodium in 30 ml of ethanol. After 3 hours of heating at reflux, 0.55 mlof concentrated hydrochloric acid is added, and heating at reflux iscontinued for a further 3 hours. The mixture is diluted with ethanol andthe solid is then separated off and discarded. The filtrate isconcentrated under reduced pressure, taken up in ethyl acetate andwashed with water and then with saturated sodium chloride solution. Themixture is dried over magnesium sulfate and then concentrated, and theresidue is purified by flash chromatography (silica gel, mobile phasecyclohexane/ethyl acetate, gradient 10:1 to 1:1). This gives ethyl7-(benzyloxy)-6-methoxy-4-oxo-4H-chromen-2-carboxylate in a yield of 58%as a colorless solid.

Mp. 168° C.

Step b):

Ethyl 7-hydroxy-6-methoxy-2-chromancarboxylate

A solution of 7.5 mmol of ethyl7-(benzyloxy)-6-methoxy-4-oxo-4H-chromen-2-carboxylate in 60 ml of ethylacetate and 30 ml of glacial acetic acid is hydrogenated in the presenceof 1.2 g of 10% palladium on carbon at 3 bar and 50° C. After 4 days,the hydrogenation is terminated and the mixture is diluted with ethylacetate. The mixture is filtered through kieselguhr and the filtrate isconcentrated under reduced pressure. The residue is taken up in ethylacetate and the organic phase is washed with water and saturated sodiumchloride solution. The mixture is dried over sodium sullfate andconcentrated, giving ethyl 7-hydroxy-6-methoxy-2-chromancarboxylate in ayield of 94% as a colorless oil which is directly reacted further.

Step c):

Ethyl 7-(benzyloxy)-6-methoxy-2-chromancarboxylate

Under argon, 8.9 mmol of a 60% strength suspension of sodium hydride inparaffin oil are added a little at a time to 1.86 g of ethyl7-hydroxy-6-methoxy-2-chromancarboxylate in 23 ml of dimethylformamide.The mixture is stirred at room temperature for 60 minutes, and 8.1 mmolof benzyl bromide are then added. The reaction mixture is stirred atroom temperature for 5 hours. For aqueous work-up (three times washingwith water, once with saturated sodium chloride solution), the mixtureis diluted with ethyl acetate. The organic phase is dried over sodiumsulfate and concentrated. Two recrystallizations from cyclohexane givepure ethyl 7-(benzyloxy)-6-methoxy-2-chromancarboxylate; further productfractions are obtained from the mother liquors of the recrystallizationsby preparative HPLC purification (column; chromsil, mobile phase:acetonitrile/water).

Total yield: 72% of theory.

Mp. 100° C.

Step d):

(+)- and (−)-Ethyl 7-(benzyloxy)-6-methoxy-2-chromancarboxylate

Preparative HPLC separation of the racemic ethyl7-(benzyloxy)-6-methoxy-2-chromancarboxylate on a chiral phase (ChiracelOD 500×20 mm; isohexane/isopropanol 6:4) gives the (S)-(−)-enantiomer[mp. 95° C., α_(D) ²⁰=−12.2° (c=0.6, dichloromethane)] and the(R)-(+)-enantiomer [mp. 94° C., α_(D) ²⁰=+11.5° (c=0.5,dichloromethane)] as colorless solids.

Step e):

(R)-(−)-[7-(Benzyloxy)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]methanol

2.6 mmol of (R)-(+)-ethyl 7-(benzyloxy)-6-methoxy-2-chromancarboxylateare dissolved in 9 ml of toluene and, under argon and at roomtemperature, added dropwise to a solution of 6.5 mmol of sodiumbis(2-methoxyethoxy)aluminum dihydride in 18 ml of toluene. After 2hours at room temperature, the mixture is diluted with ethyl acetate.The mixture is washed twice with water, undissolved particles arefiltered off and the filtrate is then washed again with water and thenwith saturated sodium chloride solution. Drying over sodium sulfate andevaporation under reduced pressure gives a solidifying oil which ispurified by flash chromatography (silica gel, mobile phasecyclohexane/ethyl acetate 2:1). This gives, in a yield of 89%,(R)-(−)-[7-(benzyloxy)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]methanol.

Mp. 109-112° C.

α_(D) ²⁰=−71° (c=0.5, dichloromethane)

optical purity >99.5% (HPLC on a chiral OD-H column).

Step f):

(R)-[7-(Benzyloxy)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]methylmethane-sulfonate

245 mg of methanesulfonyl chloride are added dropwise to a solution of1.8 mmol of(R)-(−)-[7-(benzyloxy)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]methanol in0.35 ml of pyridine and 5 ml of dichloromethane. The mixture is stirredovernight and then diluted with dichloromethane. Aqueous work-up(washing with water and sodium chloride solution), drying andconcentration gives a crude product which is purified by flashchromatography (silica gel, mobile phase toluene/ethyl acetate, gradient10:1 to 1:1). The product fraction obtained after evaporation isrecrystallized from dichloromethane/cyclohexane. This gives, in a yieldof 93%,(R)-[7-(benzyloxy)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]methylmethanesulfonate.

Mp. 147° C.

Step g):

(R)-(−)-[N-Benzyl-N-{[7-(benzyloxy)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]-methyl}amine

A mixture of 1.4 mmol of(R)-[7-(benzyloxy)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]methylmethanesulfonate,15 mg of sodium iodide and 1.6 ml of benzylamine is allowed to stand atroom temperature for 14 days. The mixture is then heated at 100° C. for5 hours. After cooling, the reaction mixture is diluted with toluene,and the precipitated solid is filtered off. The filtrate is freed ofvolatile components, finally at 100° C. and under a reduced pressure ofabout 1 mbar. The solution of the residue and the ethyl acetate issubjected to aqueous work-up (washing with water and sodium chloride)and dried. The residue obtained after concentration is purified by flashchromatography (silica gel, mobile phase toluene/ethyl acetate, gradient2:1 to 1:1). The evaporated product fractions are treated withcyclohexane, giving a solid which is recrystallized from cyclohexane.Washing with pentane gives, in a yield of 83%,(R)-(−)-[N-benzyl-N-{[7-(benzyloxy)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]-methyl}amineas colorless crystals.

Mp. 94° C.

α_(D) ²⁰=−76.5° (c=0.5, methanol).

Step h):

(R)-(−)-[2-[4-(Benzyl{[7-(benzyloxy)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]-methyl}amino)-2-butynyl]-1,2-benzisothiazol-3(2H)-one1,1-dioxide

At room temperature and under argon, 42 mg of paraformaldehye, 14 mg ofcopper(II) acetate and 308 mg of2-(2-propynyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (obtained fromthe sodium salt of saccharine and propargyl bromide) are addedsuccessively to a solution of 1.1 mmol of(R)-(−)-[N-benzyl-N-{[7-(benzyloxy)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl}aminein 3 ml of dioxane, and the mixture is then heated at 80° C. for 90minutes. After dilution with ethyl acetate, the mixture is subjected toaqueous work-up (washing with water and saturated sodium chloridesolution). The organic phase is dried over sodium sulfate andconcentrated. Flash chromatography (silica gel, mobile phasecyclohexane/ethyl acetate 1:1) gives a crude product which isrechromatographed (silica gel, mobile phase dichloromethane, thencyclohexane/ethyl acetate 1:2). In this manner, (R)-(−)-[2-[4-(benzyl{[7-(benzyloxy)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl}-amino)-2-butynyl]-1,2-benzisothiazol-3(2H)-one1,1-dioxide is obtained as an oil in a yield of 90%.

α_(D) ²⁰=−35.2° (c=0.5, methanol).

Step i):

(R)-(−)-2-(4-{[(7-Hydroxy-6-methoxy-3,4-dihydro-2H-chromen-2-yl)methyl]-amino}butyl)-1,2-benzisothiazol-3(2H)-one1,1-dioxide hydrochloride

A mixture of 0.88 mmol of(R)-(−)-2-[4-(benzyl{[7-(benzyloxy)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-2-butynyl]-1,2-benzisothiazol-3(2H)-one1,1-dioxide and 0.1 g of 10% palladium on carbon in 7 ml of methanol and2 ml of concentrated hydrochloric acid is, without external cooling,hydrogenated under atomospheric pressure. After 2 hours, the same amountof catalyst is added, and the hydrogenation is continued for a further 4hours. The reaction mixture is diluted with dichloromethane and filteredthrough kieselguhr. The filtrate is washed with saturated sodiumchloride solution and dried over sodium sulfate. The oil obtained afterevaporation is taken up in a little hot dichloromethane, and cyclohexaneis added. Distillative removal of the dichloromethane under reducedpressure results in the formation of crystals. The resulting precipitateis filtered off, washed with cyclohexane and dried under reducedpressure. This gives, in a yield of 64%,(R)-(−)-[2-(4-{[(7-hydroxy-6-methoxy-3,4-dihydro-2H-chromen-2-yl)methyl]-amino}butyl)-1,2-benzisothiazol-3(2H)-one1,1-dioxide hydrochloride.

Mp. 195-198° C. (with decomposition)

α_(D) ²⁰=−65.7° (c=0.5, methanol)

MS (ESI pos): m/z=447 [M+H]⁺

¹H-NMR (200 MHz, DMSO-d₆): δ=1.5-2.2 (m, 6H), 2.6-3.2 (m, 6H), 3.65 (s,3H), 3.75 (m, 2H), 4.2 (m, 1H), 6.25 (s, 1H), 6.6 (s, 1H), 7.9-8.15 (m,3H), 8.3 (m, 1H), 8.6-9.0 (broad, 2H).

Example 2

2-[4-({[(2R)-6-Hydroxy-3,4-dihydro-2H-chromen-2-yl]methyl}amino)butyl]-1,2-benzisothiazol-3(2H)-one1,1-dioxide hydrochloride

Step a):

Benzyl(2R)-3,4-dihydro-2H-chromen-2-ylmethyl[4-(1,1-dioxido-3-oxo-1,2-benziso-thiazol-2(3H)-yl)butyl]carbamate

40 ml of water and 2.5 g (30 mmol) of sodium bicarbonate are added to asuspension of 1.2 g (5 mmol) of(−)-(R)-2-[4-[[(3,4-dihydro-2H-1-chromen-2-yl)methyl]-amino]butyl]-1,2-benzisothiazol-3(2H)-one1,1-dioxide hydrochloride (EP 352 613 B1) in 40 ml of diethyl ether. Themixture is cooled to 0° C. At an internal temperature of at most 5° C.,a solution of 1.0 g (6 mmol) of benzyloxycarbonyl chloride in 5 ml ofdiethyl ether is added dropwise. After 2 hours of stirring at roomtemperature, the organic phase is separated off and the aqueous phase isextracted with diethyl ether. The combined organic phases are dried overmagnesium sulfate and concentrated. Chromatography (silica gel, mobilephase toluene/ethyl acetate, gradient 1:0 to 5:1) gives 2.6 g (90% oftheory) of benzyl(2R)-3,4-dihydro-2H-chromen-2-ylmethyl[4-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)butyl]carbamateas an oil which is directly reacted without further purification.

R_(f) (silica gel, toluene/ethyl acetate 3:1)=0.70

Step b):

Benzyl[(2R)-6-acetyl-3,4-dihydro-2H-chromen-2-yl]methyl[4-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)butyl]carbamate

12.7 g (95 mmol) of anhydrous aluminum chloride are suspended in 10 mlof 1,2-dichloroethane. At 0° C., initially 5.9 ml (82 mmol) of acetylchloride are added. At 0° C., a solution of 34 g (63 mmol) of benzyl(2R)-3,4-dihydro-2H-chromen-2-ylmethyl[4-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)butyl]carbamatein 100 ml of 1,2-dichloroethane is slowly added dropwise to thismixture. The reaction is stirred at room temperature overnight. Themixture is poured into ice-water and the organic phase is then separatedoff and the aqueous phase is repeatedly extracted with dichloromethane.The combined organic extracts are dried over magnesium sulfate andconcentrated. The resulting crude product is purified by chromatography(silica gel, mobile phase toluene/ethyl acetate 3:1). This gives 9.6 g(26.5% of theory) of benzyl[(2R)-6-acetyl-3,4-dihydro-2H-chromen-2-yl]methyl[4-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)butyl]carbamate.

R_(f) (silica gel, toluene/ethyl actetate 3:1)=0.32

Step c):

(2R)-2-({[(Benzyloxy)carbonyl][4-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)-butyl]amino}methyl)-3,4-dihydro-2H-chromen-6-ylacetate

At 0° C. and with exclusion of light, 2.2 g (13 mmol) ofm-chloroperoxybenzoic acid are added to 2.9 g (5 mmol) of benzyl[(2R)-6-acetyl-3,4-dihydro-2H-chromen-2-yl]methyl[4-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)butyl]carbamatein 30 ml of dichloromethane. At this temperature, 570 mg (5 mmol) oftirfluoroacetic acid are then slowly added dropwise. The mixture isstirred at room temperature overnight and then diluted withdichloromethane, and saturated sodium bicarbonate solution is added. Theorganic phase is separate off, dried over magnesium sulfate andconcentrated. Chromatography (silica gel, mobile phase toluene/ethylacetate, gradient 1:0 to 3:1) gives 2.8 g (94% of theory)of(2R)-2-({[(benzyloxy)carbonyl][4-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)butyl]-amino} methyl)-3,4-dihydro-2H-chromen-6-yl acetate as an oil.

R_(f) (silica gel, toluene/ethyl acetate 3:1)=0.44

Step d):

2-[4-({[(2R)-6-Hydroxy-3,4-dihydro-2H-chromen-2-yl]methyl}amino)butyl]-1,2-benzisothiazol-3(2H)-one1,1-dioxide hydrochloride

2 g of 10% palladium on carbon are added to 11.2 g (19 mmol) of(2R)-2-({[(benzyloxy)carbonyl][4-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)-butyl]amino}methyl)-3,4-dihydro-2H-chromen-6-ylacetate in 200 ml of glacial acetic acid and 67 ml of concentratedhydrochloric acid, and the mixture is hydrogenated at 3 bar and roomtemperature for 4 hours. The catalyst is filtered off, and 5 ml of 25%strength aqueous ammonia are then added and the mixture is concentrated.The residue is purified by chromatography (silica gel, mobile phasedichloromethane/ethanol, gradient 1:0 to 5:1). The resulting productfractions are freed from the solvent by concentration and taken up inethanol, and 10 ml of a 4 N solution of HCl gas in ethanol are addedcarefully. After cooling in ice, the resulting solid is filtered offwith suction, dissolved in 550 ml of hot ethanol and treated withactivated carbon. After filtration, the mixture is concentrated to about100 ml. The precipitated crystals are filtered off with suction anddried under reduced pressure. This give 3.15 g (37% of theory) of2-[4-({[(2R)-6-hydroxy-3,4-dihydro-2H-chromen-2-yl]methyl}amino)butyl]-1,2-benzisothiazol-3(2H)-one1,1-dioxide hydrochloride as colorless crystals.

Mp. 220 to 222° C.

MS (FAB): m/z=417 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): δ=1.5-2.1 (m, 6H), 2.6-3.2 (m, 6H), 3.75 (m,2H), 4.2 (m, 1H), 6.45-6.65 (m, 3H), 7.9-8.15 (m, 3H), 8.3 (m, 1H),8.6-9.0 (broad, 2H)

Elemental analysis: C₂₁H₂₅ClN₂O₅S C: calc. 55.7, found 56.0; H: calc..5.6, found 5.7 N: calc. 6.2, found 6.2; S: calc. 7.1, found 7.1

Example 3

Step a):

4-Hydroxychroman-2-carboxylic acid

1 g (5.2 mmol) of chromone-2-carboxylic acid is dissolved in 25 ml of1,4-dioxane and 5 ml of dry ethanol. 1 g (26.3 mmol) of sodiumborohydride is added, and the mixture is then heated at reflux for 1hour. The mixture is cooled to room temperature and solidified with 1 mlof 1 M hydrochloric acid and then with 4.5 ml of 6 M hydrochloric acid.The organic phase is separated off and the aqueous phase is extractedtwice with in each case 20 ml of diethyl ether. The organic phases arecombined and evaporated to dryness. The residue is dissolved in asolvent mixture of 1.5% acetic acid and 5% methanol (v/v) indichloromethane, and the product is isolated chromatographically, underthe following conditions: column Lobar® LiChroprep® Si 60, size B,column temperature room temperature, mobile phase 1.5% acetic acid and5% methanol (v/v) in dichloromethane, flow rate 15 ml/min, UV detectionat 230 nm. The product-containing fractions are combined and evaporatedto dryness.

Yield: 420 mg (37% of theory)

GC/MS (after methylation): m/z=208 [M]⁺ (methyl ester)

GC/MS (after silylation): m/z=338 [M]⁺ (bistrimethylsilyl derivative)

¹H-NMR (400 MHz, CD₃OD, adjusted to δ=3.30 with CD₂HOD): δ=2.16 (H-3a,1H, ddd); 2.48 (H-3e, 1H, ddd); 4.79 (H-2a, 1H, dd); 4.88 (H-4a, 1H,dd); 6.86 (H-8, 1H, d); 6.92 (H-6, 1H, dt); 7.16 (H-7, 1H, dt); 7.37(H-5, 1H, d).Step b):

250 mg of 4-hydroxychroman-2-carboxylic acid are suspended in 4.5 ml ofdiethyl ether, a solution of about 4.5 mmol of diazomethane in 4.5 ml ofdiethyl ether is added and the mixture is stirred at room temperaturefor 30 minutes. The mixture is evaporated to dryness, giving the productas an oily residue.

Yield: 268 mg (quant.)

¹H-NMR (400 MHz, CD₃OD, adjusted to δ=3.30 with CD₂HOD): δ=2.26 (H-3a,1H, ddd); 2.66 (H-3e, 1H, ddd); 3.67 (CH₃O, 3H, s); 4.79 (H-2a, 1H, dd);4.92 (H-4a, 1H, dd); 6.9 (H-8/H-6, 2H, m); 7.2 (H-7/H-5, 2H, m).

Step c):

N-Benzyl-4-(tert-butyldimethylsilanyloxy)chroman-2-carboxamide

Method 1

55 mg (0.24 mmol) of methyl 4-hydroxychroman-2-carboxylate are dissolvedin 0.25 ml of ethylene glycol dimethyl ether. 0.15 ml (1.37 mmol) ofbenzylamine and 5 mg (0.04 mmol) of lithium iodide are added, and themixture is then stirred at 60° C. for 3 hours. The product isprecipitated using 1 ml of 0.1 M hydrochloric acid and the solid isfiltered off, washed with water and dried in a desiccator over blue gel.

80 mg (0.28 mmol) of the N-benzyl-4-hydroxychroman-2-carboxylamineobtained in this manner are dissolved in 2 ml of dichloromethane, and150 μl (1.29 mmol) of 2,6-lutidine are added. 150 μl (0.65 mmol) oftert-butyldimethylsilyl trifluoromethanesulfonate are then added, andthe solution is stirred at room temperature for 8 hours. The reaction isterminated by addition of 0.53 ml of 10% strength ammonium chloridesolution, and another 0.5 ml of dichloromethane is then added. Theproduct-containing organic phase is washed 7 times with in each case0.73 ml of 0.1 M hydrochloric acid and then with 0.29 ml of a saturatedsodium bicarbonate solution and then evaporated to dryness. The crudeproduct is purified by HPLC (see below).

Method 2

268 mg (1.2 mmol) of methyl 4-hydroxychroman-2-carboxylate are dissolvedin 2.5 ml of dichloromethane. 0.6 ml (5.15 mmol) of 2,6-lutidine and 0.6ml (2.61 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate areadded, and the solution is then stirred at room temperature for 6 hours.The reaction is terminated by addition of 2 ml of a 10% strengthammonium chloride solution and the product-containing organic phase isthen washed 7 times with in each case 3 ml of 0.1 M hydrochloric acidand then with 1 ml of a saturated sodium bicarbonate solution and thenevaporated to dryness.

430 mg (1.33 mmol) of the methyl4-(tert-butyldimethylsilanyloxy)chroman-2-carboxylate obtained in thismanner are dissolved in 1.25 ml of ethylene glycol dimethyl ether, and0.765 ml (7 mmol) of benzylamine are added. 25.5 mg (0.19 mmol) oflithium iodide are added, and the reaction mixture is then stirred at70° C. for 3 hours. The product is precipitated by addition of 5 ml of0.1 M hydrochloric acid. The supernatant is decanted and the residue iswashed with 2 ml of water. The residue is then dissolved in 1 ml ofdichloromethane, and the product-containing organic phase is evaporatedto dryness.

The crude products obtained by Method 1 and Method 2 are combined andpurified by preparative HPLC chromatography under the followingconditions: column Nucleosil® 100 C-18, 125×16 mm (particle size 7 μm),column temperature room temperature, mobile phase 75% acetonitrile/25%water (v/v), flow rate 6 ml/min, UV detection at 230 nm. Theproduct-containing fractions are combined and evaporated to dryness.

Yield: 265 mg (46% of theory)

¹H-NMR (400 MHz, CD₃OD, adjusted to δ=3.30 with CD₂HOD): δ=0.20/0.23(dimethylsilyl, 3H, s/3H, s); 0.96 (t-butyl, 9H, s); 1.97 (H-3a, 1H, m);2.54 (H-3e, 1H, ddd); 4.41/4.50 (CH₂-phenyl, 2H, AB); 4.72 (H-2a, 1H,dd); 5.09 (H-4a, 1H, dd); 6.91 (H-8, 1H, d); 6.94 (H-6, 1H, t); 7.15(H-7, 1H, t); 7.20-7.35 (H-5 and phenyl, 6H, m).

Step d):

Benzyl-[4-(tert-butyldimethylsilanyloxy)-chroman-2-ylmethyl]amine

A solution of 265 mg (0.66 mmol) ofN-benzyl-4-(tert-butyldimethylsilanyloxy)-chroman-2-carboxamide in 2 mlof toluene is cooled in an ice bath, and 2 ml of sodiumbis-(2-methoxyethoxy)aluminum dihydride (70% strength solution intoluene) are added. The reaction mixture is stirred at 60° C. for 2hours and at room temperature overnight. 10 ml of 1 M aqueous sodiumhydroxide solution are then added a little at a time, and the mixture isextracted with 20 ml of dichloromethane and again with 10 ml ofdichloromethane. The combined organic phases are washed with 10 ml ofwater and evaporated to dryness. The product is obtained as an oilyresidue.

Yield: 226 mg (89% of theory)

¹H-NMR (400 MHz, CD₃OD, adjusted to δ=3.30 with CD₂HOD): δ=0.17/0.21(dimethylsilyl, 3H, s/3H, s); 0.96 (t-butyl, 9H, s); 1.75 (H-3a, 1H, m);2.18 (H-3e, 1H, ddd); 2.77 (H-9, 1H, dd); 2.90 (H-9′, 1H, dd); 3.84(CH₂-phenyl, 2H, s); 4.30 (H-2a, 1H, m); 5.01 (H-4a, 1H, dd); 6.76 (H-8,1H, d); 6.86 (H-6, 1H, t); 7.10 (H-7, 1H, t); 7.20-7.45 (H-5 and phenyl,6H, m).

Step e):

2-(4-{Benzyl-[4-(tert-butyldimethylsilanyloxy)chroman-2-ylmethyl]amino}butyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[d]isothiazol-3-one

380 mg (1.19 mmol) of2-(4-bromobutyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[d]isothiazol-3-one and263 μl (1.51 mmol) of N-ethyldiisopropylamine are added to a solution of224 mg (0.58 mmol) ofbenzyl-[4-(tert-butyldimethylsilanyloxy)chroman-2-ylmethyl]amine in 1.25ml of dry N-methylpyrrolidinone. The reaction mixture is stirred at 120°C. for 3 hours. After cooling to room temperature, 2 ml of water areadded, resulting in the precipitation of a dark, viscous product. Thesupernatant is decanted and the residue is washed twice with in eachcase 1.5 ml of water. The product is then dissolved in 3 ml ofdichloromethane, the residue water is removed by drying and the solutionis evaporated to dryness. The crude product is purified by HPLCchromatography under the following conditions: column Nucleosil® 100C-18, 125×16 mm (particle size 7 μm), column temperature roomtemperature, mobile phase 85% acetonitrile/15% water (v/v), flow rate 6ml/min, UV detection at 230 nm. The product-containing fractions arecombined and evaporated to dryness. The residue is dissolved in 2.5 mlof ethanol and 6 ml of acetone and again evaporated to dryness. Theproduct is dried in a desiccator over blue gel.

Yield: 121 mg (33% of theory)

MS (EI): m/z=621 [M+H]⁺

¹H-NMR (400 MHz, CD₃OD, adjusted to δ=3.30 with CD₂HOD): δ=0.11/0.16(dimethylsilyl, 3H, s/3H, s); 0.92 (t-butyl, 9H, s); 1.51 (H-3a, 1H, m);1.63 (H-11, 2H, m); 1.88 (H-12, 2H, m); 2.26 (H-3e, 1H, ddd); 2.6 (H-9and H-10/H-10′, 3H, m); 2.76 (H-9′, 1H, dd); 3.58/3.73 (CH₂-phenyl, 2H,AB); 3.74 (H-13, 2H, t); 4.17 (H-2a, 1H, m); 4.91 (H-4a, 1H, dd); 6.67(H-8, 1H, d); 6.82 (H-6, 1H, t); 7.04 (H-7, 1H, t); 7.15-7.40 (H-5 andphenyl, 6H, m); 7.90 (H-16, 1H, dt); 7.95 (H-15, 1H, dt); 8.03(H-14/H-17, 2H, d).

Step f):

2-(4-{[4-tert-Butyldimethylsilanyloxy)chroman-2-ylmethyl]amino}butyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[d]isothiazol-3-one

120 mg (0.19 mmol) of2-(4-{benzyl-[4-(tert-butyldimethylsilanyloxy)chroman-2-ylmethyl]amino}butyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benizo[d]isothiazol-3-oneare dissolved in 2 ml of methanol and 1 ml of acetic acid, and 100 mg ofPearlman catalyst (20% Pd(OH)₂ an activated carbon) are added. At roomtemperature, hydrogen is introduced for 4 hours. After filtration, themother liquor is concentrated to dryness. The crude product is reacteddirectly, without further purification.

Yield: 107 mg

MS (EI): m/z=531 [M+H]⁺

Step g):

2-{4-[(4-Hydroxychroman-2-ylmethyl)amino]butyll}-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[d]isothiazol-3-one

81 mg of2-(4-{[4-tert-butyldimethylsilanyloxy)chroman-2-ylmethyl]amino}butyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[d]isothiazol-3-oneare dissolved in 4 ml of 1 M hydrochloric acid and 4 ml of methanol. Thesolution is stirred at room temperature overnight. Using sodiumbicarbonate, the pH is adjusted to 8, and the mixture is then extractedthree times with in each case 3 ml of dichloromethane. The combinedorganic phases are combined with a solution of 16 mg of product from apreliminary experiment, dried over sodium sulfate and evaporated todryness.

Yield: 74 mg

¹H-NMR (500 MHz, CD₃OD, adjusted to δ=3.30 with CD₂HOD): δ=1.68 (H-11,2H, m); 1.74 (H-3a, 1H, ddd); 1.89 (H-12, 2H, m); 2.24 (H-3e, 1H, ddd);2.85 (H-9, 1H, dd); 2.75 (H-10/H-10′, 3H, t); 2.93 (H-9′, 1H, dd); 3.81(H-13, 2H, t); 4.29 (H-2a, 1H, m); 4.87* (H-4a, 1H, dd); 6.77 (H-8, 1H,d); 6.88 (H-6, 1H, t); 7.10 (H-7, 1H, t); 7.41 (H-5, 1H, dd); 7.93(H-16, 1H, dt); 7.98 (H-15, 1H, dt); 8.05 (H-14, 1H, m); 8.07 (H-17, 1H,m). *This value was measured at 50° C.

1. A compound of the general formula (I),

in which the radicals R¹, R² and R³ are as defined below: R¹ R² R³ OH HH; H OH H; H H OH; OH OH H; OH H OH; H OH OH or OH OH OH,

or a salt, hydrate or solvate thereof.
 2. A compound as claimed in claim1, where the compound has the R configuration in the 2-position of thechroman ring.
 3. A pharmaceutical composition comprising at least onecompound as claimed in claim 1 or 2 and customary auxiliaries andadditives.
 4. A method for preparing a pharmaceutical compositioncomprising at least one compound as claimed in claim 1 or 2, wherein theactive compounds are converted into a suitable administration form usingcustomary auxiliaries and additives.
 5. A method for treating stroke orskull-brain trauma comprising administering to a subject in need thereofan effective amount of a compound of claim 1 or 2.